The systemic lupus erythematosus susceptibility allele of IRF5 exhibits increased expression in myeloid cells and contributes to the interferon signature. This is a proposal to investigate the expression and functionality of the susceptibility allele in B cells. We hypothesize that the susceptibility allele enhances transitional B cell survival and mature B cell responsiveness to antigen. Most importantly, we propose that the susceptibility allele exhibits increased responsiveness to estrogen in synergy with type 1 interferon. We will explore these hypotheses studying primary B cells from healthy risk allele positive and negative individuals.